%0 Journal Article %J Sci Signal %D 2015 %T Genome-wide RNAi screening implicates the E3 ubiquitin ligase Sherpa in mediating innate immune signaling by Toll in Drosophila adults %A Kanoh, Hirotaka %A Tong, Li-Li %A Kuraishi, Takayuki %A Suda, Yamato %A Momiuchi, Yoshiki %A Shishido, Fumi %A Kurata, Shoichiro %K Animals %K drosophila melanogaster %K Drosophila Proteins %K Genome-Wide Association Study %K Gram-Positive Bacteria %K Gram-Positive Bacterial Infections %K Protein-Serine-Threonine Kinases %K RNA, Small Interfering %K SUMO-1 Protein %K toll-like receptors %K Ubiquitin-Protein Ligases %X The Drosophila Toll pathway plays important roles in innate immune responses against Gram-positive bacteria and fungi. To identify previously uncharacterized components of this pathway, we performed comparative, ex vivo, genome-wide RNA interference screening. In four screens, we overexpressed the Toll adaptor protein dMyd88, the downstream kinase Pelle, or the nuclear factor κB (NF-κB) homolog Dif, or we knocked down Cactus, the Drosophila homolog of mammalian inhibitor of NF-κB. On the basis of these screens, we identified the E3 ubiquitin ligase Sherpa as being necessary for the activation of Toll signaling. A loss-of-function sherpa mutant fly exhibited compromised production of antimicrobial peptides and enhanced susceptibility to infection by Gram-positive bacteria. In cultured cells, Sherpa mediated ubiquitylation of dMyd88 and Sherpa itself, and Sherpa and Drosophila SUMO (small ubiquitin-like modifier) were required for the proper membrane localization of an adaptor complex containing dMyd88. These findings highlight a role for Sherpa in Drosophila host defense and suggest the SUMOylation-mediated regulation of dMyd88 functions in Toll innate immune signaling. %B Sci Signal %V 8 %P ra107 %8 2015 Oct 27 %G eng %N 400 %1 http://www.ncbi.nlm.nih.gov/pubmed/26508789?dopt=Abstract %R 10.1126/scisignal.2005971